A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat

Conley, Justin M.; Lambright, Christy; Evans, Nicola; Cardon, Mary C.; Medlock-Kakaley, Elizabeth; Wilson, Vickie S.; Gray, L. Earl

doi:10.1016/j.envint.2021.106615

Cited by 46 publications

(17 citation statements)

References 81 publications

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“…However, phthalates such as DEHP are also widely found in foods, particularly meat and dairy products, poly(vinyl chloride) medical devices and equipment, and personal care products, − exposure sources that may fall outside of TSCA’s direct regulatory authorities but contribute to background phthalate human exposures and thus are relevant to the question of whether exposure sources under TSCA’s regulatory jurisdiction present “unreasonable risk”. Evidence supports biological additivity of phthalate exposures affecting common biological targets. − Furthermore, studies have documented differences in exposure levels by race, with higher exposure levels in African Americans than whites; similar results have been reported elsewhere. ,− Collectively, therefore, regulatory decisions based on risk estimates of individual phthalate exposure may under protect public health. While EPA initially did not signal that it would incorporate cumulative risk assessment (CRA) as part of its current risk evaluation for the seven phthalates, the agency recently announced that it is reconsidering if CRA for phthalates would be appropriate.…”

Section: Introductionsupporting

confidence: 52%

Cumulative Risk Evaluation of Phthalates Under TSCA

Payne-Sturges

Saram

Cory‐Slechta

2023

Environ. Sci. Technol.

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The U.S. Environmental Protection Agency (EPA) is currently conducting separate Toxic Substances Control Act (TSCA) risk evaluations for seven phthalates: dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), diisobutyl phthalate (DIBP), dicyclohexyl phthalate (DCHP), di-isodecyl phthalate (DIDP), and diisononyl phthalate (DINP). Phthalates are highly abundant plastic additives used primarily to soften materials and make them flexible, and biomonitoring shows widespread human exposure to a mixture of phthalates. Evidence supports biological additivity of phthalate mixture exposures, including the enhancement of toxicity affecting common biological targets. Risk estimates based on individual phthalate exposure may not be protective of public health. Thus, a cumulative risk approach is warranted. While EPA initially did not signal that it would incorporate cumulative risk assessment (CRA) as part of its current risk evaluation for the seven phthalates, the agency recently announced that it is reconsidering if CRA for phthalates would be appropriate. Based on our review of existing chemical mixtures risk assessment guidance, current TSCA scoping documents for the seven phthalates, and pertinent peer-reviewed literature, we delineate a CRA approach that EPA can easily implement for phthalates. The strategy for using CRA to inform TSCA risk evaluation for existing chemicals is based upon integrative physiology and a common adverse health outcome algorithm for identifying and grouping relevant nonchemical and chemical stressors. We recommend adjustments for how hazard indices (HIs) or margins of exposure (MOEs) based on CRA are interpreted for determining “unreasonable risk” under TSCA.

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Section: Introductionsupporting

confidence: 52%

Cumulative Risk Evaluation of Phthalates Under TSCA

Payne-Sturges

Saram

Cory‐Slechta

2023

Environ. Sci. Technol.

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“…If combinatorial EDCs confer an enhanced effect on metabolic health, risk assessment based on no adverse effect levels for single EDC exposures could overestimate "safe" exposure levels. Multiple studies focused on reproductive toxicity support this possibility, as the reproductive toxicity of EDC mixtures indicates dose-additive effects of low dose mixtures [35][36][37][38], even when single EDC exposures show no phenotype [39][40][41]. This study hypothesizes that well-studied EDCs known to target metabolic function through different direct molecular targets will produce enhanced metabolic toxicity on a single physiological function, such as glucose metabolism [35,42].…”

Section: Introductionmentioning

confidence: 75%

Protracted Impairment of Maternal Metabolic Health in Mouse Dams Following Pregnancy Exposure to a Mixture of Low Dose Endocrine-Disrupting Chemicals, a Pilot Study

Merrill

Anderson

Conrad

et al. 2021

Toxics

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Pregnancy, a period of increased metabolic demands coordinated by fluctuating steroid hormones, is an understudied critical window of disease susceptibility for later-life maternal metabolic health. Epidemiological studies have identified associations between exposures to various endocrine-disrupting chemicals (EDCs) with an increased risk for metabolic syndrome, obesity, and diabetes. Whether such adverse outcomes would be heightened by concurrent exposures to multiple EDCs during pregnancy, consistent with the reality that human exposures are to EDC mixtures, was examined in the current pilot study. Mouse dams were orally exposed to relatively low doses of four EDCs: (atrazine (10 mg/kg), bisphenol-A (50 µg/kg), perfluorooctanoic acid (0.1 mg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.036 µg/kg)), or the combination (MIX), from gestational day 7 until birth or for an equivalent 12 days in non-pregnant females. Glucose intolerance, serum lipids, weight, and visceral adiposity were assessed six months later. MIX-exposed dams exhibited hyperglycemia with a persistent elevation in blood glucose two hours after glucose administration in a glucose tolerance test, whereas no such effects were observed in MIX-exposed non-pregnant females. Correspondingly, MIX dams showed elevated serum low-density lipoprotein (LDL). There were no statistically significant differences in weight or visceral adipose; MIX dams showed an average visceral adipose volume to body volume ratio of 0.09, while the vehicle dams had an average ratio of 0.07. Collectively, these findings provide biological plausibility for the epidemiological associations observed between EDC exposures during pregnancy and subsequent maternal metabolic dyshomeostasis, and proof of concept data that highlight the importance of considering complex EDC mixtures based of off common health outcomes, e.g., for increased risk for later-life maternal metabolic effects following pregnancy.

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“… 50 Similarly, a more recent study showed cumulative effects in male rats of mixtures of environmental contaminants with relevance for male sexual development at dilutions of their NOAELs as low as a factor of 15, on marks related to this end point. 51 In this context, it should be kept in mind that although an effect at the NOAEL is commonly assumed to be zero, there may very well be an effect at the NOAEL that was, however, too small to be detected owing to the lack of observational or statistical power for that small effect size (e.g., Crepet at al. 52 ).…”

Section: Discussionmentioning

confidence: 99%

Dose Addition in the Induction of Craniofacial Malformations in Zebrafish Embryos Exposed to a Complex Mixture of Food-Relevant Chemicals with Dissimilar Modes of Action

Ven

Ommeren

Zwart

et al. 2022

Environ Health Perspect

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Background: Humans are exposed to combinations of chemicals. In cumulative risk assessment (CRA), regulatory bodies such as the European Food Safety Authority consider dose addition as a default and sufficiently conservative approach. The principle of dose addition was confirmed previously for inducing craniofacial malformations in zebrafish embryos in binary mixtures of chemicals with either similar or dissimilar modes of action (MOAs). Objectives: In this study, we explored a workflow to select and experimentally test multiple compounds as a complex mixture with each of the compounds at or below its no observed adverse effect level (NOAEL), in the same zebrafish embryo model. Methods: Selection of candidate compounds that potentially induce craniofacial malformations was done using in silico methods—structural similarity, molecular docking, and quantitative structure–activity relationships—applied to a database of chemicals relevant for oral exposure in humans via food (EuroMix inventory, ). A final subselection was made manually to represent different regulatory fields (e.g., food additives, industrial chemicals, plant protection products), different chemical families, and different MOAs. Results: A final selection of eight compounds was examined in the zebrafish embryo model, and craniofacial malformations were observed in embryos exposed to each of the compounds, thus confirming the developmental toxicity as predicted by the in silico methods. When exposed to a mixture of the eight compounds, each at its NOAEL, substantial craniofacial malformations were observed; according to a dose–response analysis, even embryos exposed to a 7-fold dilution of this mixture still exhibited a slight abnormal phenotype. The cumulative effect of the compounds in the mixture was in accordance with dose addition (added doses of the individual compounds after adjustment for relative potencies), despite different MOAs of the compounds involved. Discussion: This case study of a complex mixture inducing craniofacial malformations in zebrafish embryos shows that dose addition can adequately predicted the cumulative effect of a mixture of multiple substances at low doses, irrespective of the (expected) MOA. The applied workflow may be useful as an approach for CRA in general. https://doi.org/10.1289/EHP9888

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A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat

Cited by 46 publications

References 81 publications

Cumulative Risk Evaluation of Phthalates Under TSCA

Cumulative Risk Evaluation of Phthalates Under TSCA

Protracted Impairment of Maternal Metabolic Health in Mouse Dams Following Pregnancy Exposure to a Mixture of Low Dose Endocrine-Disrupting Chemicals, a Pilot Study

Dose Addition in the Induction of Craniofacial Malformations in Zebrafish Embryos Exposed to a Complex Mixture of Food-Relevant Chemicals with Dissimilar Modes of Action

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